The invention provides a device which makes non-invasive, quantitative, and precise measurements of optical properties across the three-dimensional volume of objects which transmit light. The invention is within the general field of optical computed tomography (optical CT). The invention is directed to devices which measure and quantify optical properties which include, but are not limited to, absorption of visible light, absorption of ultraviolet light, absorption of infrared light, refractive index, light scattering, fluorescence, phosphorescence, and combinations of these. One application of the invention is to quantify the three-dimensional distribution of a radiation dose absorbed by an object in which optical properties of the object have been made to change predictably with the interaction with ionizing radiation. This application allows the planning and execution of a radiotherapy treatment to be simulated, measured, and evaluated on an inanimate object before applying it to humans and is particularly important for validating complex radiotherapy treatment plans. Without such an experimental measurement, it is impossible to be sure that the dose received by a patient is that claimed by the treatment planning software. In this application, the invention provides information by measuring the optical density of the sample at all points in the three-dimensional volume. The object is specially designed so that its optical properties (in particular, its absorption or scattering coefficients at the wavelength of operation of the system) change with the absorption of radiation in a predictable and quantitative manner. A full review of the history and principles of optical CT scanning in radiotherapy dosimetry was presented (S J Doran and N Krstajić, J. Phys. Conf. Ser. 56 (2006) 45-57).
Optical CT has been utilized to produce computer-rendered images of various structures which permit the transmission of incident light. Optical CT allows the generation of three-dimensional images through tomographic reconstruction of a stepped series of two-dimensional data arrays (“slices”). Various techniques have been devised for the imaging of structures of various sizes, ranging from small (less than 1 mm field-of-view) to large (for example, a transparent cylinder having a radius of 10 cm).
One field in which optical CT has made an impact is the evaluation of the difference in optical properties within a three-dimensional translucent or transparent object. Three-dimensional dosimeters have been provided in which certain optical properties within the dosimeter volume change predictably upon interaction with ionizing radiation. These optical properties include degree of light scattering, absorbance, refractive index, and combinations of these. These three-dimensional dosimeters have found use in the evaluation of complex radiotherapy treatment plans such as Intensity-Modulated Radiation Therapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT). In order to be useful, these three-dimensional dosimeters must be scanned to evaluate the optical data contained within. Optical CT scanners have been developed to meet this need. The Optical CT scanners all store in computer memory a series of two-dimensional images which are transformed by various algorithms and reconstructed into three-dimensional images by a computer program.
An Optical CT laser scanner for three dimensional dosimetry has been described (Gore et al, 1996, Physics in Medicine and Biology 41 2695-2704; U.S. Pat. No. 6,218,673 to Gore et al). The device disclosed employs a laser light source which is made to scan through a cylindrical dosimeter. The incident laser beam is reflected through 90 degrees by a first mirror and passed through the dosimeter contained within a water bath. The transmitted beam is reflected through 90 degrees by a second into a detector. A two-dimensional slice is produced by moving the first and second mirrors simultaneously along a carriage in a plane parallel to the optical axis. The dosimeter is rotated through a small angle in a plane orthogonal to the optical axis and another scan is measured. This scan and rotate process is repeated until the dosimeter has been rotated through 180 degrees. The entire volume of the dosimeter can only be scanned by employing a series of stepped rotations and axial translation of the dosimeter. Thus, after a large number of scans and stepped rotations of the dosimeter (180 scans when the step angle is set to 1 degree), the dosimeter must be indexed axially (e.g. so that the next scanned plane is 1 mm higher than the previous plane), and the scan-and-rotate process repeated. When the scanning is complete, a three-dimensional image is reconstructed after the data is subjected to filtration and back-projection algorithms. While this scanner has successfully evaluated several dosimeters, it suffers from a number of drawbacks which limit its usefulness. Transmission data requires correction to account for deviation of the laser beam from a normal incidence angle. The angle of incidence of the laser beam upon the surface of the tank was adjusted to 5 degrees from the window normal to reduce multiple reflections. The stepper-driven lateral mirror translation apparatus is vulnerable to error (precision motion of a relatively large structure is needed), resulting in a potential loss of resolution. The axial translation of the dosimeter required to measure slices perpendicular to the dosimeter axis represents another source of error. It is necessary to carefully align the center of the scan length with the axis of rotation of the dosimeter. The scanned area of each slice must be restricted to 90% of the diameter of the dosimeter. Errors in beam wandering across the face of the detector need to be compensated by the addition of a diffusing window and a converging lens. The most objectionable feature of this scanner is its long acquisition time. The total data acquisition time for a 60×60 pixel image was six minutes. Imaging of another object required approximately 2 seconds per profile, leading to an imaging time of about 12 minutes per slice. Total acquisition time for dosimeters of clinically relevant volume can exceed eighteen hours. True three-dimensional scans, with isotropic high resolution and a large field-of-view in the slice direction are not feasible using this methodology, particularly on a routine clinical basis.
Optical CT scanners employing area detectors have been developed. Scanners with CCD or CMOS area detectors have become feasible with the widespread availability of high-quality digital cameras. Whereas laser systems acquire data in a point-by-point fashion, imaging area detectors allow the acquisition of a complete two-dimensional projection at once. Each two-dimensional projection gives the data required for creating a row in the sinogram for every slice in a three-dimensional reconstruction. Currently scientific CCD cameras have a typical matrix size of 1000×1000 pixels, so improvements of over two orders of magnitude in acquisition time over the Gore et al instrument (U.S. Pat. No. 6,218,673, vide supra) are theoretically possible. In practice, the speed when using a CCD-based system is often limited by the data-throughput rate, in particular the rate at which the data may be transferred out of the camera to the host computer. A disadvantage of the CCD system is its sensitivity to various types of artifacts. As opposed to the point illumination achievable with laser optical CT scanning, brightfield illumination utilized with CCD-based optical CT scanners can give rise to increased noise due to light scattering, stray light detection and, most significantly, differential refraction of incident light by regions of the sample with subtly different refractive indices (schlieren artefacts).
An optical CT scanner with a CCD area detector was disclosed (Bero, M. et al, 1999, DOSGEL 1999, 1st International Workshop on Radiation Therapy Gel Dosimetry, Kentucky). This scanner, based on parallel-beam geometry, utilized a LED light source with a lens arrangement to deliver parallel beams through a dosimeter immersed in refractive-index matching liquid. The dosimeter was rotated through a small discrete angle between the acquisitions of two-dimensional slices. The data was treated with filtration and back-projection algorithms and was reconstructed into a three-dimensional image.
A similar optical CT scanner employing cone-beam geometry was introduced (Wolodzko, J. et al, 1999, Medical Physics, 26(11), 2508-2513), developed (Jordan, K. et al, 2001 DOSGEL 2001, Second International Conference on Radiotherapy Gel Dosimetry, Brisbane, 2001) and commercialized (Modus Medical Devices Inc., London, ON).
Recently optical CT scanners with laser light sources and improved acquisition times have been developed. The decrease in time required to scan an object relative to the Gore et al instrument (U.S. Pat. No. 6,218,673, vide supra) was achieved by adopting rotating mirrors to guide scanning in a raster fashion.
A scanner employing a single rotating mirror to scan laser light through a cylindrical sample was disclosed (Maryanski et al, 2001, Proc. SPIE, 4320, 764-774). This scanner was used for three-dimensional mapping of optical attenuation coefficient within translucent cylindrical objects. The scanner design utilized the cylindrical geometry of the imaged object to obtain the desired paths of the scanning light rays. A rotating mirror and a photodetector were placed at two opposite foci of the translucent cylinder that acts as a cylindrical lens. A laser beam passed first through a focusing lens and then was reflected by the rotating mirror, so as to scan the interior of the cylinder with focused and parallel paraxial rays that were subsequently collected by the photodetector to produce the projection data, as the cylinder rotates in small angle increments between projections. Filtered backprojection was then used to reconstruct planar distributions of optical attenuation coefficient in the cylinder. Multi-planar scans are used to obtain a complete three-dimensional tomographic reconstruction. The scanner was designed for use in radiation therapy dosimetry and quality assurance for mapping three-dimensional radiation dose distributions in various types of tissue-equivalent gel phantoms that change their optical attenuation coefficients in proportion to the absorbed radiation dose. This scanning system, in part due to the reliance upon the cylindrical shape of the gel dosimeter to function as a lens in the optical path, is able to scan only a fraction of the volume contained within the dosimeter, thereby limiting its usefulness. Moreover, the scanner uses only a single mirror, leading to deflection of the laser beam in only one dimension. Thus, to image multiple slices, the sample must again be translated axially, as for the original scanner of Gore et al (U.S. Pat. No. 6,218,673 vide supra). Motion of the mirror is uni-direction, rather than back and forth. This means that for a significant fraction of each cycle ˜⅚, no useful data is being acquired. This limits the utility of the scanner.
An optical CT laser scanner employing a single rotating plane mirror has been described (van Doorn, T. et al, 2005, Australasian Physical Engineering Sciences in Medicine, 28, 76-85). In this scanner, laser light reflects from the rotating mirror and is directed to either a stationary plane mirror or to a first converging lens. When the light is directed to the stationary mirror, it is reflected into the detector for reference measurement. When the light beam is reflected from the rotating mirror into the acceptance aperture of the first lens, it is refracted to pass through an object immersed in a refractive index matching bath. The rotating mirror, mounted at the focal point of the first lens, directs the laser beam to scan a plane through the object, forming a set of parallel rays. A second converging lens refracts the light into the detector. Although the scanner was designed to have the capacity to form 1.0 mm3 voxels over the volume of a cylinder with a diameter of 100 mm and a height of 70 mm, the authors report a single reconstructed plane image produced from incremental stepped revolution of the object in 1.25 degree intervals, mirror rotation speed of 120 revolutions per second, and a total scan speed (one slice) of 2.4 seconds. Presumably the device will need to be altered to permit sampling of the entire volume of the object. This might be accomplished by advancing the object axially to scan consecutive planes through the object perpendicular to the object axis. Because the mirror rotates, it is inefficient in data acquisition in the same way as the scanner of Maryanski (vide supra).
An optical CT scanner comprised of a laser light source, a single rotating mirror, a lens pair, and a tilting yoke was disclosed (Conklin, J. et al, 2006, Journal of Physics Conference Series 56, 211-213). Two aspherical Fresnel lenses (200 mm focal length, 254 mm diameter, 8 grooves per mm) were placed on either side of an aquarium containing water into which the object to be scanned was placed. Two thin front surfaced mirrors were attached back to back to a steel cylinder attached directly to a small DC motor shaft. The rotating mirror assembly was mounted on a U shaped yoke that allowed the mirrors to tilt as well. The mirror assembly was positioned at the focal point of the input Fresnel lens. Stepper motors control mirror tilt and sample rotation. The tilting of the yoke allowed scanning of planes orthogonal to the axis of the dosimeter. Vertical beam stops at the aquarium edges provided start and stop reference positions. The photodiode detector was placed at the focal point of the exit Fresnel lens. The mirror rotated continuously at 10 Hz. The scanner algorithm involved recording a specified number of points after the signal exceeded a specified threshold followed by a mirror tilt. This sequence was repeated from top to bottom of the sample forming a raster scan. Next the sample was rotated and the raster scan was again repeated. Typical scan values: 1200 points per 150 mm, 200 projections per 180 degrees and 25 minutes per 75 slices. The samples were aqueous patent blue violet solutions and the cylinders were PFA Teflon tubes 96 mm OD and 0.5 mm wall thickness. Profile data points were converted from time to position by assuming a constant mirror rotation frequency and measuring the distance between the start and stop beam stops located at the aquarium edges. Poor resolution due to the use of Fresnel lenses and variability in motion control of the rotating mirror and tilting yoke limits the usefulness of this technique.
The present invention shares some optical attributes currently utilized in Confocal Microscopy and related techniques, which rely on excitation of a selected region of a fluorescent-labeled specimen by an incident beam of a first wavelength and detection of the emitted light of a second wavelength. U.S. Pat. No. 4,997,242 to Amos, W. describes Confocal Microscopy utilizing an optical assembly composed of two rotating plane mirrors, five stationary plane mirrors, two beam splitters and two stationary paraboloidal mirrors. An incident laser light beam is directed by the mirror-beam splitter assembly to a specimen. The mechanical working of the rotating mirrors allows the light beam to scan the sample in a raster pattern. The sample has been previously treated so that the interaction with the incident beam causes fluorescence to take place. With this technique, the depth of penetration of incident light is limited by the characteristics of the sample (usually a biological specimen) and the fluorescence is measured at 360 degrees to the incident beam. The emitted light from the fluorescing sample follows the same optical path as the incident beam, though in the opposite direction, and is diverted by mirrors and beam splitters into two photomultipliers. The function of the scanning assembly is to provide a raster scan of the specimen, into which the light penetrates a short distance, usually a maximum of a few hundred microns, to facilitate the emission of light having a wavelength different from the excitation wavelength. Recent improvements in confocal microscopy include two-photon and multi-photon techniques (Potter, S. et al, 1996, Scanning, 18, 147.) In a related technique, Selective Plane Illumination Microscopy, (Huisken, J. et al, 2004, Science, 305, 1007), a thin sheet of light is made to pass through a specimen at the focal plane of a microscope detecting orthogonal to the incident light plane. The sample has been previously treated so that the interaction with the incident beam causes fluorescence to take place. The emitted light is captured by the microscope's detector with little out-of-focus fluorescence detected. The result is data representing a “slice” of the specimen. The selected plane of incident light and the microscope focal plane are then adjusted to measure subsequent slices through the specimen. This technique allows the reconstructing a 3-D image from a set of 2-D projections at different sample rotations, using a reconstruction technique such as filtered back-projection. This technology is a variant of optical sectioning, which is well known in the art, and in which out-of-focus interference can be removed by computer deconvolution of a digitized image. This is an iterative computational technique in which a stack of focal sections is recorded and the contribution of out-of-focus signal to a given section from structures in other sections is computed and subtracted from that section. This has proved to be a powerful technique where the out-of-focus signal rejection required is not too great. However, it requires that a high level of registration is maintained as a focal series is being recorded.
A variant of optical CT currently employed is optical projection tomography (OPT), in which incident light travels through the object and is detected as a projection. Objects studied by this technique may be small, wherein the optical assembly might include a microscope component, or large, wherein magnification may not be desirable.
An OPT microscope transmits beams of light through a specimen at different angles. Projections of the specimen are recorded at the different angles. The projections are processed using tomographic computations to reconstruct the spatial distribution of the linear attenuation coefficient within the specimen. A series of projection slices are reconstructed to form a three-dimensional image of the object. Each element in each recorded projection corresponds to a line integral of the attenuation coefficient along the beam path. The line integral represents a total attenuation of the beam as it goes along a straight line through the specimen. A three-dimensional distribution of the attenuation coefficient provides information about the three-dimensional structure of the specimen. The projection data must be mathematically treated to allow the rendering of an accurate three-dimensional image. Algorithms to perform such treatment of data are well known (Kak, A. et al, 1988, Principles of Computerized Tomographic Imaging, IEEE Press) and improvements have been recently reported (see, inter alia, Walls, J. et al, 2005, Phys. Med. Biol. 50(19), 4645-65 and Wang, Y. et al, 2006, Phys. Med. Biol. 51(23), 6023-32). Objects imaged by detection of projections vary in size, depending upon the optical property measured and the ability of the object to transmit the incident light. Biological tissue samples, in which transmission is hampered by absorption and scattering, which are examined by OPT microscopy may be on the order of 1 cm3. Transparent objects imaged by corresponding macro optical techniques might be as large as a cylinder with a radius of 8 cm and a height of 16 cm.
Optical Projection Tomography Microscopy was disclosed (Sharpe et al, 2002, Science 296, 541; WO/2002/0996; WO/2002/0997). In this technique, light is transmitted through a specimen and is detected by either a one-dimensional or two-dimensional array of detectors (e.g. charge-coupled device or CCD). The data is then filtered and treated with a back-projection algorithm to achieve a three-dimensional image. The specimen is immersed in an index-matching liquid to reduce the scattering of light. This means that light passes through the specimen in approximately straight lines and a standard backprojection algorithm can generate relatively high-resolution images. Inside the OPT scanning device, the specimen is maintained within the liquid, rotated to a series of angular positions (usually less than 1 degree apart), and an image is captured at each orientation. The apparatus is carefully aligned to ensure that the axis of rotation is perpendicular to the optical axis so that projection data pertaining to each plane is collected by a linear row of pixels on the charge-coupled device (CCD) of the camera. Light is shone into the back of the specimen, directly toward the objective lens, and the image formed records the attenuation of this beam. However, in reality, even specimens maintained in an index-matching liquid still cause diffraction, refraction, and scattering of photons as they pass through. The lenses act as collimators, so only rays that emerge from the specimen at specific positions and angles are sampled. In this invention, the optimal lamp for OPT is not a point source, but a wide-field illumination that, owing to the intrinsic scattering within the specimen, can in fact be a diffuse source. The technique can be used to image fluorescent-labeled samples.
A three-dimensional optical CT microscope employing a mirror with two axes of rotation was described (Chamgoulov, R. et al, 2005, Proc. SPIE 5701, 24-43; Chamgoulov, R. et al, WO/2006/03722, US2007258122). This system consists of two high numerical-aperture lenses, an optical scanner, a light source, and a light detector. A two-axis mirror equipped with motorized linear actuators serves as the optical scanner. In this invention, highly collimated light was passed through a beam expander and made to focus at the pupil plane of condenser lens by the assembly of a two-axis plane mirror and a scan lens. Incident light is thus made to pass through the sample in parallel lines. The angle of incidence φ of illumination upon the sample is varied within the acceptance aperture of the lens assembly (0<φ<135 degrees), so that series of projections are made at varying angles through the sample. Light transmitted through the sample is refracted by an objective lens and recorded by a suitable light detector. New reconstruction algorithms containing feedback and error correction were needed to address the limited-angle reconstruction problem. The effects of these corrections on quantitative data remain to be tested, but it can be anticipated that unacceptable artifacts would occur for applications in which accuracy of order 1% is required, such as 3-D radiation dosimetry. This scanner is explicitly limited to microscopic imaging. This scanner is not a telecentric system, which is an important feature in metrological applications.
There remains an unmet need for an optical CT scanner capable of providing fast, reliable, and accurate three-dimensional images of macroscopic objects, such as those used in 3-D radiation dosimetry. The present invention provides an optical CT scanner which utilizes a novel arrangement of optical, mechanical, and electronic components to provide a rapid and precise raster scan of three-dimensional objects, leading to a set of two-dimensional projections, which can be processed to reconstruct high-resolution three-dimensional reconstructed images. The invention further provides means to achieve highly accurate and precise (i.e., with high signal-to-noise ratio) three-dimensional images in which unwanted optical artifacts, such as noise from stray light and scattering, are minimized.